The present invention comprises a new class of compounds useful in treating diseases, such as TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain, cancer, and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Interleukin-1 (IL-1) and Tumor Necrosis Factor a (TNF-xcex1) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharidexe2x80x94LPS) or external cellular stress (e.g., osmotic shock and peroxide).
Elevated levels of TNF-xcex1 and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic xcex2 cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter""s syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-xcex1.
It has been reported that TNF-xcex1 plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-xcex1 levels increased in the contused hemisphere (Shohami et al., J. Cereb. Blood Flow Metab. 14, 615 (1994)). In a rat model of ischemia wherein the middle cerebral artery was occluded, the levels of TNF-xcex1 mRNA of TNF-xcex1 increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)). Administration of TNF-xcex1 into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels. TNF-xcex1 promotes the infiltration of other cytokines (IL-1xcex2, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein, Stroke 25, 1481 ). TNF-xcex1 has also been implicated to play a role in type II diabetes (Endocrinol. 130, 43-52, 1992; and Endocrinol. 136, 1474-1481, 1995).
TNF-xcex1 appears to play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-xcex1 secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al., J. Immunol. 142, 431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role of TNF-xcex1 in the HIV associated states of cachexia and muscle degradation.
TNF-xcex1 is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-xcex1 may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6, and IL-8.
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter""s syndrome; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. Viruses sensitive to TNF-a inhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.
TNF-xcex1 and IL-1 appear to play a role in pancreatic xcex2 cell destruction and diabetes. Pancreatic xcex2 cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic xcex2 cells often accompanies type I diabetes. Pancreatic xcex2 cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue. Thus glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing the glucagon receptors, it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than is TNF-xcex1 (Firestein, Am. J. Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531 (1994)).
IL-1 also appears to play a role in promoting certain viral life cycles. For example, cytokine-induced increase of HIV expression in a chronically infected macrophage line has been associated with a concomitant and selective increase in IL-1 production (Folks et al., J. Immunol. 136, 4049 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 553 (1983)) discussed the role of IL-1 in muscle degeneration.
In rheumatoid arthritis, both IL-1 and TNF-xcex1 induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen-induced arthritis (CIA) in rats and mice), intra-articular administration of TNF-xcex1 either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
Several approaches have been taken to block the effect of TNF-xcex1. One approach involves using soluble receptors for TNF-xcex1 (e.g., TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-xcex1-mediated disease states. A second approach to neutralizing TNF-xcex1 using a monoclonal antibody specific to TNF-xcex1, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Maini et al., Immunological Reviews, pp. 195-223 (1995)). These approaches block the effects of TNF-xcex1 and IL-1 by either protein sequestration or receptor antagonism.
The present invention also relates to a method of treating cancer which is mediated by Raf and Raf-inducable proteins. Raf proteins are kinases activated in response to extracellular mitogenic stimuli such as PDGF, EGF, acidic FGF, thrombin, insulin or endothelin, and also in response to oncoproteins such as v-src, v-sis, and v-fms. Raf functions downstream of ras in signal transduction from the cellular membrane to the nucleus. Compounds in the present invention may be oncolytics through the antagonism of Raf kinase. Antisense constructs which reduce cellular levels of c-Raf and hence Raf activity inhibit the growth of rodent fibroblasts in soft agar, while exhibiting little or no general cytotoxicity. This inhibition of growth in soft agar is highly predictive of tumor responsiveness in whole animals. Moreover Raf antisense constructs have shown efficacy in reducing tumor burden in animals. Examples of cancers where Raf kinase is implicated by overexpression include cancers of the brain, larynx, lung, lymphatic system, urinary tract and stomach, including hystocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Other examples include cancers involving overexpression of upstream activators of Raf or Raf-activating oncogenes, including pancreatic and breast carcinoma.
Substituted imidazole and pyrrole compounds have been described for use in the treatment of cytokine mediated diseases by inhibition of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF. Substituted imidazoles for use in the treatment of cytokine mediated diseases have been described in U.S. Pat. No. 5,593,992; WO 93/14081; WO 96/18626; WO 96/21452; WO 96/21654; WO 96/40143; WO 97/05878; WO 97/05878; (each of which is incorporated herein by reference in its entirety). Substituted imidazoles for use in the treatment of inflammation has been described in U.S. Pat. No. 3,929,807 (which is incorporated herein by reference in its entirety). Substituted pyrrole compounds for use in the treatment of cytokine mediated diseases have been described in WO 97/05877; WO 97/05878; WO 97/16426; WO 97/16441; and WO 97/16442 (each of which is incorporated herein by reference in its entirety).
Substituted 2-aminopyridine compounds have been described as nitric oxide synthase inhibitors for use in the treatment of inflammation, neurodegenerative disorders and disorders of gastrointestinal motility in WO 96/18616 and WO 96/18617.
Diaryl substituted pyridine compounds have been described for use in the treatment of inflammation and inflammation related disorders in WO 96/24584 and U.S. Pat. No. 5,596,008.
U.S. Pat. No. 3,980,652, U.S. Pat. No. 3,991,057 and U.S. Pat. No. 4,002,629 describe piperazinyl substituted pyridine compounds for use as anti-inflammatory and cardiovascular agents.
JP 6135934 describes substituted pyridine compounds as phospholipase A2 inhibitors for use as antiphlogistic and anti-pancreatitis agents. GB 1,189,188 describes pyrimidin-2-ylamino substituted pyridine compounds as therapeutically valuable compounds for use as antiphlogistic agents.
The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain, cancer, and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases, such as inflammatory, pain and diabetes diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure: 
wherein R1, R5, R6, R7, X and Y are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.
In accordance with the present invention, there is provided compounds of the formula: 
or a pharmaceutically acceptable salt thereof, wherein
X is O, S, S(O), S(O)2 or NR2; preferably, X is O, S or NR2; more preferably, X is O or NR2; most preferably, X is NR2;
Y is xe2x80x94C(O)xe2x80x94NR3R4 or xe2x80x94NR4xe2x80x94C(O)xe2x80x94R3;
R1 is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R18xe2x80x94Z18xe2x80x94 or R18xe2x80x94Z18-alkyl;
preferably, R1 is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of C1-C6 alkyl, halo, C1-C6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18xe2x80x94Z18xe2x80x94 or R18xe2x80x94Z18xe2x80x94C1-C6 alkyl;
more preferably, R1 is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which is optionally substituted by 1-4 radicals of C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R18xe2x80x94Z18xe2x80x94 or R18xe2x80x94Z18xe2x80x94C1-C4 alkyl;
provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is 1-3, preferably, 1-2, and provided when Y is xe2x80x94NR4xe2x80x94C(O)xe2x80x94R3 and X is O or S, R1 is other than a 2-pyrimidinyl radical;
more preferably, R1 is a radical of the formula 
wherein R22, R23, R24, R25 and R26 are each independently a radical of hydrogen, C1-C4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino, R18xe2x80x94Z18xe2x80x94 or R18xe2x80x94Z18xe2x80x94C1-C4 alkyl; provided at least one of R21, R22, R23, R24 and R25 is hydrogen; and provided that the combined total number of aryl and heteroaryl radicals in R22, R23, R24, R25 and R26 is 0-1;
R2 is a hydrogen or alkyl radical; preferably, R2 is a hydrogen or C1-C4 alkyl radical; more preferably, R2 is a hydrogen or C1-C2 alkyl radical; more preferably, R2 is a hydrogen or methyl radical; and most: preferably, R2 is a hydrogen radical;
R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino, R19xe2x80x94Z19xe2x80x94 or R19xe2x80x94Z19-alkyl; preferably, R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C6 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19xe2x80x94Z19xe2x80x94 or R19xe2x80x94Z19xe2x80x94C1-C6 alkyl; more preferably, R3 is an aryl or heteroaryl radical which is optionally substituted by 1-5 radicals of C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R19xe2x80x94Z19xe2x80x94 or R19xe2x80x94Z19xe2x80x94C1-C4 alkyl;
provided that the total number of aryl and heteroaryl radicals in R3 is 1-3, preferably, 1-2; and provided when Y is xe2x80x94C(O)xe2x80x94NR3R4, R3 is other than a phenyl or naphthyl having an amino, nitro, cyano, carboxy or alkoxycarbonyl substituent bonded to the ring carbon atom adjacent to the ring carbon atom bonded to xe2x80x94NR4xe2x80x94;
more preferably, R3 is a radical of the formula 
wherein
U is Cxe2x80x94R13 or N;
V and W are each independently Cxe2x80x94R12 or N;
R11 and R13 are each independently a radical of hydrogen, C1-C4 alkyl, halo, trifluoromethyl, cyano, azido, nitro, amidino or R19xe2x80x94Z19xe2x80x94; preferably, R11 and R13 are each independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, azido, nitro, amidino, R19xe2x80x94Oxe2x80x94, R19xe2x80x94S(O)2xe2x80x94, R19xe2x80x94Oxe2x80x94C(O)xe2x80x94, R19C(O)xe2x80x94, R19xe2x80x94NR21xe2x80x94C(O)xe2x80x94 or R19xe2x80x94NR21xe2x80x94S(O)2xe2x80x94;
each R12 is independently a radical of hydrogen, C1-C6 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, R31xe2x80x94Z31xe2x80x94 or R31xe2x80x94Z31xe2x80x94C1-C4 alkyl; preferably, each R12 is independently a radical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl, (methylamino)methyl or (dimethylamino)methyl;
provided that the combined total number of aryl and heteroaryl radicals in R11, R12 and R13 is 0-1;
wherein each R31 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
each Z31 is independently xe2x80x94Oxe2x80x94, xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR21xe2x80x94, xe2x80x94NRxe2x80x94S(O)2xe2x80x94 or xe2x80x94S(O)2xe2x80x94NR21xe2x80x94;
R4 is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or R20 xe2x80x94Z20-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, R4 is a radical of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl of 1-3 halo radicals, C2-C6 haloalkenyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20xe2x80x94Z20xe2x80x94C1-C6 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20xe2x80x94Z20xe2x80x94C2-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy;
more preferably, R4 is a radical of hydrogen, C1-C6 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or R20xe2x80x94Z20xe2x80x94C2-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
more preferably, R4 is a radical of hydrogen, methyl or ethyl radical;
wherein each R18 is independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R18 is independently a hydrogen, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyl, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R18 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, azido, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy;
each Z18 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR21, xe2x80x94NR21xe2x80x94S(O)2xe2x80x94 or xe2x80x94S(O)2xe2x80x94NR21xe2x80x94; preferably, each Z18 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94S(O)2xe2x80x94 or xe2x80x94S(O)2xe2x80x94NR21;
wherein each R19 is independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R19 is independently a hydrogen, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, cyano, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy;
more preferably, each R19 is independently a hydrogen, C1-C4 alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical; wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
more preferably, each R19 is independently a hydrogen, methyl, ethyl, trifluoromethyl, phenyl, heteroaryl, phenylmethyl or heteroaryl-methyl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
each Z19 is independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94S(O)2xe2x80x94 or xe2x80x94S(O)2xe2x80x94NR21xe2x80x94; preferably, each Z21 is independently xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94S(O)2xe2x80x94 or xe2x80x94S(O)2xe2x80x94NR21xe2x80x94; more preferably, each Z is independently xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94 or xe2x80x94NR21xe2x80x94S(O)2xe2x80x94;
wherein each R20 is independently a hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy;
preferably, each R20 is independently a hydrogen, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals;
more preferably, each R20 is independently a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, acetylamino, halo, C1-C4 alkyl, trifluoromethyl or trifluoromethoxy;
more preferably, each R20 is independently a hydrogen, C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C2 alkyl or heteroaryl-C1-C2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;
each Z20 is independently xe2x80x94Oxe2x80x94, xe2x80x94S, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR21xe2x80x94, xe2x80x94NR21xe2x80x94S(O)2xe2x80x94 or xe2x80x94S(O)2xe2x80x94NR21xe2x80x94; preferably, each Z20 is independently xe2x80x94Oxe2x80x94 or xe2x80x94NR21xe2x80x94;
wherein each R21 is independently a hydrogen or alkyl radical; preferably, each R21 is independently a hydrogen or C1-C4 alkyl radical; more preferably, each R21 is independently a hydrogen or methyl radical;
R5 and R6 are each independently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
preferably, R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, C1-C4 aminoalkyl, (C1-C4 alkyl)amino-C1-C4 alkyl, di(C1-C4 alkyl)amino-C1-C4 alkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, C1-C4 alkylsulfonylamino, aminosulfonyl, C1-C4 alkylaminosulfonyl, di(C1-C4 alkyl)aminosulfonyl, hydroxy, C1-C4 hydroxyalkyl, thiol, C1-C4 alkylthiol, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, (C1-C4 alkoxy)C1-C4 alkyl, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical;
more preferably, R5 and R6 are each independently a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C5 alkanoylamino, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl) aminocarbonyl or di (C1-C4 alkyl) aminocarbonyl radical;
more preferably, R5 and R6 are each independently a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C1-C2 alkylamino, di(C1-C2 alkyl)amino, hydroxy, methoxy or ethoxy radical; most preferably, R5 and R6 are each a hydrogen radical;
R7 is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;
preferably, R7 is a hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, C1-C4 aminoalkyl, (C1-C4 alkyl)amino-C1-C4 alkyl, di(C1-C4 alkyl)amino-C1-C4 alkyl, aminosulfonyl, C1-C4 alkylaminosulfonyl, di(C1-C4 alkyl)aminosulfonyl, hydroxy, C1-C4 hydroxyalkyl, thiol, C1-C4 alkylthiol, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, (C1-C4 alkoxy)C1-C4 alkyl, cyano, azido, nitro, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical;
more preferably, R7 is a hydrogen, C1-C4 alkyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, carboxy, (C1-C4 alkoxy)carbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl or di(C1-C4 alkyl)aminocarbonyl radical;
more preferably, R7 is a hydrogen, methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxy radical; most preferably, R7 is a hydrogen radical.
The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
Compounds of interest include the following:
2-cyclohexyloxy-5-(2-chlorophenylcarbonylamino)pyridine;
2-cyclohexyloxy-5-(2-methylphenylcarbonylamino)pyridine;
2-cyclohexyloxy-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-cyclohexyloxy-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2,4-dimethylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;
2-(2,4-dimethylphenoxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenoxy)-5-(2-methylphenylcarbonylamino) pyridine;
2-(2,6-dimethyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino) pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2-chlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;
2-(2-methylphenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methylphenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(2-methylphenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;
2-(2-methyl-4-fluorophenoxy)-5-(2-fluorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenoxy)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(1-naphthyloxy)-5-(2-methylphenylcarbonylamino) pyridine;
2-(1-naphthyloxy)-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-(1-naphthyloxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenoxy)-5-((3,5-dimethyl-4-isoxazolyl)carbonylamino)pyridine;
2-(2-methyl-4-chlorophenylthiol)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenylthiol)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-cyclohexylamino-5-(2,6-dichlorophenylcarbonylamino) pyridine;
2-cyclohexylamino-5-(2,6-dimethylphenylcarbonylamino) pyridine;
2-(2-methylcyclohexylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methylcyclohexylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2-fluorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2-chlorophenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;
2-(2-methylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;
2-(2,4-dimethylphenylamino)-5-(2,6-dimethylphenylcarbonylamino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl carbonylamino)pyridine;
2-(2-methyl-4-chlorophenylamino)-5-(2,6-dimethylphenyl carbonylamino)pyridine; and
2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenyl aminocarbonyl)pyridine.
As utilized herein, the following terms shall have the following meanings:
xe2x80x9cAlkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1-15 carbon atoms (C1-C15), more preferably 1-8 carbon atoms (C1-C8), even more preferably 1-6 carbon atoms (C1-C6), yet more preferably 1-4 carbon atoms (C1-C4), still more preferably 1-3 carbon atoms (C1-C3), and most preferably 1-2 carbon atoms (C1-C2). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
xe2x80x9cHydroxyalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and most preferably one hydrogen radical is replaced by a hydroxyl radical. Examples of such radicals include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.
xe2x80x9cAlkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2: double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), yet more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
xe2x80x9cAlkoxyxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cOxe2x80x9d is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an alkoxy radical as defined above and xe2x80x9cC(O)xe2x80x9d is a carbonyl radical.
xe2x80x9cAlkoxycarbonylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x9d is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAlkylthioxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Sxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cSxe2x80x9d is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)2xe2x80x9d is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)2xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)2xe2x80x9d is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
xe2x80x9cArylxe2x80x9d, alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo fused or heterocyclo fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, oxo and the like. Examples of aryl radicals are phenyl, o-tolyl, 4-methoxyphenyl, 2-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 2-CF3-phenyl, 2-fluorophenyl, 2-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 2-amino-3-(aminomethyl)phenyl, 6-methyl-3-acetamidophenyl, 6-methyl-2-aminophenyl, 6-methyl-2,3-diaminophenyl, 2-amino-3-methylphenyl, 4,6-dimethyl-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4-(2-methoxyphenyl)phenyl, 2-amino-1-naphthyl, 2-naphthyl, 3-amino-2-naphthyl, 1-methyl-3-amino-2-naphthyl, 2,3-diamino-1-naphthyl, 4,8-dimethoxy-2-naphthyl and the like.
xe2x80x9cAralkylxe2x80x9d and xe2x80x9carylalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.
xe2x80x9cAralkoxyxe2x80x9d, alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy and the like.
xe2x80x9cAralkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an aralkoxy radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical.
xe2x80x9cAlkanoylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical. Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
xe2x80x9cAlkanoylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAminocarbonylxe2x80x9d, alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
xe2x80x9cAminosulfonylxe2x80x9d, alone or in combination, means an amino substituted sulfonyl radical.
xe2x80x9cBenzoxe2x80x9d, alone or in combination, means the divalent radical C6H4xe2x95x90 derived from benzene. xe2x80x9cBenzo fusedxe2x80x9d forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like.
xe2x80x9cBicyclicxe2x80x9d as used herein is intended to include both fused ring systems, such as naphthyl and xcex2-carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl.
xe2x80x9cCycloalkylxe2x80x9d, alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic carbocyclic alkyl radical, preferably monocyclic, containing preferably 5-12 carbon atoms (C5-C12), more preferably 5-10 carbon atoms (C5-C10), even more preferably 5-7 carbon atoms (C5-C7), which is optionally benzo fused or heterocyclo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl, azabicyclo[3.2.1]octyl and the like.
xe2x80x9cHeteroatomsxe2x80x9d means nitrogen, oxygen and sulfur heteroatoms.
xe2x80x9cHeterocyclo fusedxe2x80x9d forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. xe2x80x9cHeterocyclylxe2x80x9d is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems. xe2x80x9cHeterocyclylxe2x80x9d radicals may optionally be substituted on at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. More preferably, xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally saturated carbocyclic fused, preferably 3-4 carbon atoms (C3-C4) to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 3-(2-methyl)pyridyl, 3-(4-trifluoromethyl)pyridyl, pyrimidinyl, 5-(4-trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidiazolyl, benzoxazolyl and the like.
xe2x80x9cHeteroaralkylxe2x80x9d, and xe2x80x9cheteroarylalkyl,xe2x80x9d alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
xe2x80x9cHalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d, alone or in combination, means fluoro, chloro, bromo or iodo radicals.
xe2x80x9cHaloalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
xe2x80x9cPharmacologically acceptable saltxe2x80x9d means a salt prepared by conventional means, and are well known by those skilled in the art. The xe2x80x9cpharmacologically acceptable saltsxe2x80x9d include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of xe2x80x9cpharmacologically acceptable salts,xe2x80x9d see infra and Berge et al, J. Pharm . Sci. 66, 1 (1977).
xe2x80x9cCytokinexe2x80x9d means a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response. Examples of cytokines include but are not limited to interleukin 1 (IL-1), preferably IL-1xcex2, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-xcex1 (tumor necrosis factor-xcex1).
xe2x80x9cTNF, IL-1, IL-6, and/or IL-8 mediated disease or disease statexe2x80x9d means all disease states wherein TNF, IL-1, IL-6, and/or IL-8 plays a role, either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1, IL-6, and/or IL-8 inducing another cytokine to be released. For example, a disease state in which IL-1 plays a major role, but in which the production of or action of IL-1 is a result of TNF, would be considered mediated by TNF.
xe2x80x9cLeaving groupxe2x80x9d generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
xe2x80x9cProtecting groupxe2x80x9d generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, arylalkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
The symbols used above have the following meanings:
Procedures for preparing the compounds of this invention are set forth below. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
The compounds of the present invention represented by Formula I above can be prepared utilizing the following general procedures. Hetero-aromatic Nitrogen Compounds; Pyrroles and Pyridines: Schofield, Kenneth; Plenum Press, New York, N.Y.; (1967) and Advances in Nitrogen Heterocycles: JAI Press, Greenwich, Conn.; (1995) describe procedures and references that may be useful in preparing compounds of the present invention.
2-Halo-5-nitro-pyridine analogs, (2) can be treated with the appropriate amine, alcohol, phenol, or thiol (Rxe2x80x94Xxe2x80x94H) in the presence of base or Cu(I) in an appropriate solvent, such as THF, DMF, DME, DMSO and the like, at a temperature from xe2x88x9220xc2x0 C. to 120xc2x0 C. to form 2-substituted-5-nitropyridines (3) (Scheme I). Reduction of the nitro group can be perfomed by treatment of (3) with hydrogen gas in the presence of palladium on carbon or Raney nickel, or alternatively, by treatment with SnCl2 in an alcoholic solvent and in the presence or absence of HCl to obtain 2-substituted-5-aminopyridines (4). The aminopyridines (4) may be alkylated using alkylhalides and an appropriate base or by reductive alkylation employing the appropriate aldehyde or ketone in the presence of a reducing agent, such as sodium triacetoxy borohydride, borane. THF and the like, to form the substituted aminopyridines (5). Either (4) or (5) may be acylated with an appropriate acid halide (e.g., R3C(O)Cl or R3C(O)Br) in the presence of a base, such as pyridine, DMAP and the like, or alternatively may be acylated with an anhydride, either mixed or symmetrical, or alternatively may be acylated by treatment with the appropriate acid (R3CO2H) in the presence of a coupling agent such as a carbodiimide reagent: to form the final product (1). Alternatively, substituted 2-bromo-5-nitropyridine analogs may be reduced to, substituted 2-bromo-5-aminopyridine analogs by the action of SnBr2 in methanolic solvent. Subsequent acylation with an appropriate activated ester (i.e.: R3CO2H in the presence of diisopropylcarbodiimide in methylene chloride as solvent) produces 2-bromopyridine-5-carboxamide compounds of structure (5a). Coupling of (5a) with an appropriate phenol in the presence of Cu(Ac)2 and K2CO3 in DMF at 140xc2x0 C. provides compounds of formula (1) where X=O. 
6-Substituted-2-halo-5-nitro-pyridine analogs (6) may be prepared from 2,6-dichloro-5-nitropyridine 15 according to the methods outlined in Scheme II. Treatment with one equivalent of an appropriate nucleophile of R7 or a precursor thereof (such as, HOxe2x88x92, ROxe2x88x92, AcSxe2x88x92, NCxe2x88x92, RSxe2x88x92 and the like) provides (6). Subsequent reaction to form (7) (treatment with R1xe2x80x94Xxe2x80x94H in the presence of base or Cu(I) in an appropriate solvent, such as THF, DMF, DME, DMSO and the like, at a temperature from xe2x80x9420xc2x0 C. to 120xc2x0 C.) and (8) (reduction of the nitro group and substitution with R4) is as described in Scheme I (cf. Colbry, N. L. et al.; J. Heterocyclic Chem., 21: 1521-1525 (1984); Matsumoto, Jun-ichi, et al.; J. Heterocyclic Chem., 21: 673-679 (1984)). (8) may be reacted with an acid halide or an activated 
ester as shown in Scheme I to provide compounds of formula (1). Where R7xe2x95x90CN, compounds of formula (8) may be hydrolyzed to acids (R7xe2x95x90CO2H) of formula (9) using acidic media such as HBr and the like. Utilizing the appropriate N-protecting groups, acids of formula (9) may be transformed into esters, amides and alcohols. Compounds of formula (9) and derivatives described above may be be reacted with an acid halide or an activated ester as shown in Scheme I to provide compounds of formula (1). Compounds of formula (8), where R7xe2x95x90xe2x80x94CN, may be reduced to the primary amine (R7xe2x95x90xe2x80x94CH2NH2) using reagents such as BH3 or hydrogen gas in the presence of palladium on carbon or Raney nickel. Subsequent manipulation and reaction of the primary amine may be performed in the presence of the pyridine-5-amine substituent due to it""s greater reactivity. Specifically, compounds of formula (8) where R=xe2x80x94CH2NH2 may be alkylated by treatment with an appropriate aldehyde or ketone in the presence of a reducing agent, such as sodium triacetoxy borohydride, or may be acylated by treatment with an appropriate activated ester, chloroformate, isocyanate and the like, or may be sulfonylated by treatment with an appropriate sulfonyl halide. Alternatively, substituted 3-aminopyridine intermediates may be prepared from the corresponding nicotinamide compound using Hofmann""s reaction.
When R6 and/or R7 is an alkyl group, such as methyl, in compound (7), containing the appropriate protecting groups of or avoiding the presence of base sensitive groups, can be treated with strong base such as NaNH2, PhLi, NaH or the like at temperatures from xe2x88x9278xc2x0 C. to 22xc2x0 C. then treated with electrophiles, such as alkyl halides, aldehydes, ketones and the like (cf. Fuerst, Feustel; CHEMTECH; 10: 693-699 (1958); Nishigaki, S. et al.; Chem. Pharm. Bull.; 17: 1827-1831 (1969); Kaiser, Edwin M.; Tetrahedron; 39: 2055-2064 (1983)). Alternatively, the alkyl group may be halogenated and the haloalkyl group may be reacted with a nucleophile, such as an amino group, alkoxy, alkylthiol and the like.
6-Chloronicotinoyl chloride analogs (10) are treated with the appropriate amine (R3R4NH) in the presence of base in an appropriate solvent, such as dichloromethane, acetonitrile, DMF, THF and the like, at a temperature from xe2x88x9220xc2x0 C. to 120xc2x0 C. to form nicotinamides (11) as shown in Scheme III. Alternatively, 6-chloronicotinic acid analogs (12) may be coupled with the appropriate amine via an anhydride, either mixed or symmetrical, or alternatively by treatment with the appropriate amine in the presence of a coupling agent such as a carbodiimide reagent to form the amide (11). 6-Chloronicotinamide analogs (11) are treated with the appropriate R1xe2x80x94Xxe2x80x94H in the presence of absence of base, or Cu(I) in an approriate solvent, such as pyridine, ethylene glycol, DMF, DME, DMSO and the like, at a temperature from xe2x88x9220xc2x0 C. to 180xc2x0 C. to form the final product (13). 
Substituted halopyridines may be readily prepared from the corresponding pyridones using phosphorus oxychloride or pentachloride.
Amines of formula NHR1R2 and NHR3R4 are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials. For example, an amide, nitro or cyano group can be reduced under reducing conditions, such as in the prescence of a reducing agent like lithium aluminum hydride and the like, to form the corresponding amine. Alkylation and acylation of amino groups are well known in the art. Chiral and achiral substituted amines can be prepared from chiral amino acids and amino acid amides (for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like) using methods well known in the art, such as H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M. Freifelder and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 985, 1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W. Wheeler and D. O""Bannon, Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, O. Ichihara and I. Walters, J. Chem. Soc., Chem., Commun. 1153, 1993.
Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids, heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans, heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides, heterocyclylhalides, heteroarylhalides, and the like are commercially available or can be readily prepared from starting materials commercially available using standard methods well known in the art.
Thioether derivatives can be converted into the corresponding sulfone or sulfoxide by oxidizing the thioether derivative with a suitable oxidation agent in a suitable solvent. Suitable oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, oxone (potassium peroxy monosulfate), meta-chloroperoxybenzoic acid, periodic acid and the like, including mixtures thereof. Suitable solvents include acetic acid (for sodium meta-perborate) and, for other peracids, ethers such as THF and dioxane, and acetonitrile, DMF and the like, including mixtures thereof.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily prepared from known starting materials.
Prodrugs of the compounds of this invention are also contemplated by this invention A prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following adminstration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.